In the beginning pg. 5
The exact instruction imparted by the Hh signal depends on what type of cell is receiving the signal and the location of that cell.
“Hh regulates a number of cell types, but most importantly, stem cells or progenitor cells,” says Cooper, who is studying the role of Hh in primary brain tumors called gliomas. “We’ve learned that these pathways regulate not only stem cells in development, but also in tumorigenesis.”
Stem cell theory
Most tissues have stem or progenitor cells well into adulthood. When adult tissues like the epithelium require repair or renewal because of an injury or normal cellular turnover, these cells most likely respond by activating or reactivating the developmental pathways that led to that tissue’s formation in the first place—pathways like Hh and Wnt.
“Stem cells or progenitor cells can respond to Hh by self-renewing, that is by dividing to form more stem or progenitor cells,” Cooper says. “In a setting where mutations can occur and accumulate, the process becomes dysregulated, and the self-renewal process may become turned on in a way that it can’t be turned off.”
When the pathway can’t be turned off, the anomalous cell divisions can lead to tumor formation. This is known as the “stem cell” theory of tumorigenesis. Indeed, the Hh pathway appears to be activated in many cancer types, particularly within cells that have a stem- or progenitor-like appearance.
While a research fellow at Johns Hopkins University, Cooper was examining how compounds known to cause birth defects (teratogens) interfere with Hh signaling. The research unexpectedly pointed towards the Hh pathway as a possible chemotherapeutic target.
Working with Philip Beachy, Ph.D., professor of Molecular Biology and Genetics at Johns Hopkins, Cooper was looking at how the teratogenic compounds jervine and cyclopamine cause a range of birth defects of the face and brain, from mild holoprosencephaly, such as cleft lip, to the most severe and fatal form of holoprosencephaly, cyclopia (development of a single, centrally-positioned eye).
Beachy and colleagues had demonstrated earlier that cholesterol played a critical role in Hh signaling during development; to be active, the Hh protein must be cleaved and one end of the protein modified by cholesterol. If this modification was inhibited, birth defects such as holoprosencephaly resulted.
Cooper suspected that these teratogens, whose chemical structures are similar to the structure of cholesterol, were somehow interfering with cholesterol modification of Hh, thus inhibiting Hh signaling required for development.
“We thought that we had this mechanism all figured out before we’d done a single experiment,” Cooper says. “But we were wrong. And it was the most spectacular mistake ever!”
They eventually determined that the compounds inhibited Hh signaling not by interfering with cholesterol modification in the Hh-generating cell, but by inhibiting receiving cells from responding. And because the Hh pathway was known to be activated in a number of cancers, it immediately became clear that these chemicals, which can produce such horrible birth defects, might have some redeeming value in treating cancer.
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